According to researchers, mapping the link between genetics and aggregation may identify several proteins that could be novel therapeutic targets for Alzheimer’s disease.
Proteins that clump together are part of the mechanism behind the formation of plaque in the brain in Alzheimer’s disease.
When proteins such as beta-amyloid aggregate in the brain, they become toxic and kill the brain cells.
For many years, researchers have been trying to understand what happens when such proteins aggregate, resulting in Alzheimer’s. Beta-amyloid and other proteins are not cleaved correctly and play a role in developing Alzheimer’s.
But protein folding is a complex process with many steps that can go well or wrong. Promising new research has investigated some of the mechanisms involved by linking the genetics behind Alzheimer’s to the processes that result in misfolded proteins aggregating into toxic amyloid fibril formation in the brain.
The results may be useful clinically.
“Our research links the molecular pathology to the genetics behind Alzheimer’s by elucidating the underlying mechanisms and proteins involved in developing the disease. The proteins and mechanisms may become targets for drugs in the future,” explains a researcher behind the study, Nathan Lewis, Associate Professor of Paediatrics and Bioengineering at the University of California, San Diego, USA and affiliate of the National Biologics Facility at the Technical University of Denmark, Kongens Lyngby.
The research has been published in Cell Systems.
Protein folding is complicated
Protein folding requires synthesising the proteins and then secreting them from the cell.
Before secretion, the proteins have to go through the entire protein secretion pathway. This involves hundreds of proteins that ensure that the finished protein is properly folded and functioning correctly.
Nathan Lewis and colleagues studied how the secretory pathway should work and what goes wrong when proteins are misfolded, clump together and become toxic to the brain.
“We examined this whole complex system to determine why the proteins are misfolded, including the genetic background,” says Nathan Lewis.
Algorithm found correlations in a large data set
“Large-scale genome-wide association studies show that various mutations are linked to the development of Alzheimer’s, but there are not many mutations in the secretory pathway as such, and this therefore hardly explains why things go wrong. The challenge therefore is to discover where things go wrong instead,” explains Nathan Lewis.
To address this challenge, the research relies on algorithms that can interrogate large data sets covering all the proteins involved in folding the beta-amyloid protein.
The algorithms can identify protein–protein interactions that occur specifically to support secreted proteins, such as beta-amyloid. This enabled the researchers to determine how the individual links in the secretory pathway are related to the final folding of the proteins. By leveraging data from large-scale mapping of proteins, the researchers used their algorithms to conclude, based on the data, the likelihood that a given tissue can secrete a given protein such as beta-amyloid.
Secretory pathway disabled
Nathan Lewis says that, although the large-scale genome-wide association studies have not been able to find significant mutations in the secretory pathway, something must regulate the production of beta-amyloid in Alzheimer’s.
The researchers analysed the secretory pathway in cells that naturally produce beta-amyloid.
By analysing the protein expression of the cells, the researchers found that cell death in the brain in Alzheimer’s is accompanied by simultaneous downregulation of the proteins that support beta-amyloid protein in the secretory pathway.
Thus, the proteins themselves do nothing wrong, but they are not synthesised and secreted well enough, resulting in aggregated beta-amyloid, which forms toxic plaque in the brain.
“The secretory pathway is downregulated, and a functionality that supports protein misfolding is upregulated. When we examined brain cells including microglia and neurons, we discovered that the secretory pathway of neurons in the brain is suppressed, especially neurons associated with developing Alzheimer’s,” says Nathan Lewis.
Also relevant for cancer
The researchers returned to the analysis of the genome-wide association studies, in which they had previously identified no mutations in the proteins themselves in the secretory pathway.
Instead, they discovered that some of the mutations associated with Alzheimer’s do not arise in these proteins but instead in the genes that regulate the activity of the entire secretory pathway.
“We thus linked genes known to be associated with risk to the regulators of the secretory pathway for beta-amyloid. This shows that the whole system becomes imbalanced in Alzheimer’s, which may explain the link between the molecular pathology of Alzheimer’s and the genetic cause,” explains Nathan Lewis.
Nathan Lewis says that this discovery has several perspectives. The study suggests potential therapeutic targets in the search for a cure for Alzheimer’s. One suggestion is that such a drug should re-establish the function of the secretory pathway by targeting the regulatory genes linked to improper protein folding.
Another perspective is that the technique of linking genes to pathology can be used for many diseases in which proteins aggregate, without the genes necessarily showing why this happens.
“This applies to diseases such as cancer and metabolic diseases. If the disease pathology is associated with protein aggregation, we can use this approach to discover why the proteins misfold and aggregate. This will point towards novel therapeutic targets for drugs against the diseases,” concludes Nathan Lewis.
